Ataxia Telangiectasia (A-T) is an autosomal recessive, pleiotrophic human disorder characterized by progressive neurodegenerative cerebellar ataxia, radiosensitivity, immunodeficiencies, telangiectases of eyes and skin, a greatly enhanced predisposition for lymphomas and premature death. Individuals heterozygous for this defect appear at risk for development of breast cancer. The gene whose defect is responsible for A-T, termed ATM (Ataxia Telangiectasia Mutated) was identified by positional cloning. Recently, a second mammalian gene closely related to ATM, termed ATR (Ataxia Telangiectasia Rad-3-related), has been identified. ATM and ATR appear to have complementary but distinct roles in early meiosis, and thus may have partially redundant functions. The hypothesis guiding this proposal is that ATM and ATR are cell cycle checkpoint genes whose products sense DNA damage and transduce this information via an intrinsic protein kinase activity. This proposal has two long-term objectives: 1) clarify the mechanisms by which defects in the ATM gene result in either cell death (neurodegeneration), or escape from apoptosis (T cell malignancy), and 2) further understanding of mammalian cell cycle checkpoint signaling pathways. The specific goals of this proposal are to 1) investigate the basis for malignant T cell development in ATM null mice already available and generate an ATM null mouse strain that develops ataxic and neurodegenerative defects similar to human A-T, 2) identify potential targets of ATM and ATR protein kinase activity for insights into checkpoint signaling pathways of the proteins, and 3) analyze the potential role of ATM function in regulation of a novel anti-apoptotic signaling pathway that may be essential in survival of tumor cells and cell death in neuronal cells.